This application is a competitive renewal of an R01 that is nearing the end of its 10th year of funding. Previously the focus of research was on gray matter abnormalities in schizophrenia. In the current five-year application, we now turn to the investigation of white matter abnormalities in schizophrenia, where we will use magnetic resonance diffusion tensor imaging (MR-DTI). MR-DTI is a relatively new neuroimaging technique that affords a unique opportunity to investigate white matter. Furthermore, unlike conventional MRI, where white matter appears uniform and homogeneous, MR-DTI is particularly revealing of the physical properties of white matter, as measured by the motion of water along axons. Hence, the density, size, and orientation of white matter can be explored. Of particular note, we consider it an exciting opportunity to be able to evaluate the empirically long-postulated hypothesis that many of the symptom features in schizophrenia may be due to disturbances in connectivity between brain regions. Accordingly, we plan to evaluate three fronto-temporal connections in the brain, including the uncinate, cingulate, and arcuate fasciculi. Additionally, we will evaluate the corpus callosum, the largest white matter fiber tract in the brain, mediating interhemispheric connections postulated to be abnormal in schizophrenia, as well as the anterior limb of the internal capsule, a fiber tract connecting medial dorsal thalamus with prefrontal cortex, and the anterior nucleus of the thalamus with the cingulate gyrus, regions also thought to be abnormal in schizophrenia. Moreover, we will evaluate specific cognitive functions thought to be associated with each of these brain regions. We will use MR-DTI to quantify diffusion (the degree of directionality of water movement, as measured by fractional and relative anisotropy) in the aforementioned major fiber connections in the brain, and for all five fiber tracts, we will measure gray matter regions of interest that are interconnected by these fiber tracts. We will also measure magnetization transfer ratio, thought to be indicative of myelin content, and we will explore the extent to which fiber tractography, a measure of the extent and direction of fiber tracts, reveals white matter abnormalities in schizophrenia. Over the 5-year period of the grant we will examine right-handed male and female patients with schizophrenia (n=50 first episode and n=100 chronic patients), as well as a contrast group of bipolar patients with psychotic features (n=50). The addition of a contrast group will allow us to evaluate the specificity of findings to schizophrenia. Additionally, we will include age, gender, and parental-socioeconomic status group matched controls (n=100). We will also test a subset of 50 patients with schizophrenia and 50 controls on both the 1.5T and 3T magnets. Finally, we will use structural equation modeling to evaluate the specific hypotheses of the study, where we will be able to determine whether or not they provide the best model for explaining the relationship among variables. Through the use of such advanced neuroimaging techniques, our long-term goal is to understand the neuropathology of schizophrenia.